Bruton's tyrosine kinase (BTK) is a member of the TEC family of nonreceptor tyrosine kinases, which consists of 650 amino acid residues and contains pleckstrin homology (PH) domain, zinc-finger region, SH3 domain, SH2 domain, and kinase domain. Recently, kinase domain, among said domains, is gaining more interests as a drug target.
BTK is found in B-cells and hematopoietic cells, rather than some T-cells, natural killer cells, plasma cells, etc. When BTK is stimulated by the B-cell membrane receptor (BCR) signals that are caused by various inflammatory responses or cancers, BTK plays an important role in production of cytokines such as TNF-α, IL-6, etc., as well as NF-κB by initiating downstream signaling such as phospholipase C gamma 2 (PLCγ2).
In the treatment of inflammation, BTK is known for mediating responses of the membrane receptors, e.g., B-cell antigen receptors which detect inflammation-inducing substances, CD40, TLR-4, Fcg and the like. Also, BTK has a strong influence on the signaling mechanism of inflammation caused by stimulation of mast cell, B-cell and macrophage. Therefore, inhibition of BTK may block IgE signaling which may slow down the progression of diseases caused by abnormal activation of BTK. This signaling mechanism is a complicated signaling pathway of immunosubstance secretion. In this process, protein phosphorylation and dephosphorylation take place in a multi-step procedure, and since BTK is one of the high-level steps in the signaling pathway, along with spleen tyrosine kinase (SYK) and, thus, it is more effective for preventing activation of factors that cause immune responses than other kinase targets.
Further, in the treatment of cancer, it is known that BTK modifies BCR and B-cell surface proteins which generate antisuicide signals. Thus, inhibition of BTK may bring about anticancer effects against cancers that are associated with BCR signaling such as lymphoma. In fact, Ibrutinib (PCI-32765) developed by Pharmacyclics Inc. was recently approved as an anti-cancer agent for the treatment of chronic lymphocytic leukemia (CLL), and a phase III trial of AVL-292 developed by Avila Therapeutics for small lymphocytic leukemia (SLL) and CLL is currently underway. It has been proven that these compounds are quite effective against SLL and CLL that are relatively rare type of cancers. However, they have failed to achieve satisfactory results against diffuse large B-cell lymphoma (DLBCL) which is more prevalent type of lymphoma. Thus, there is a growing demand for a noble drug.
The action mechanism of BTK inhibitor as an anti-inflammatory agent as well as an anti-cancer agent is thoroughly described in the reference [Nature Chemical Biology 7, (2011), 4].